ABSTRACT
UNLABELLED: ESSENTIALS: It is unclear whether interleukin-10 (IL-10) could affect clopidogrel metabolism and response. The bioactivation of and response to clopidogrel were determined between mice with or without IL-10. Maximum clopidogrel active metabolite levels were the major driver of platelet response to clopidogrel. IL-10 did not modulate maximum levels of clopidogrel active metabolite and its antiplatelet effects. BACKGROUND: Elevated plasma interleukin-10 (IL-10) levels were observed in patients who responded less to clopidogrel (a prodrug that is required for further metabolic bioactivation in the liver). However, no data are currently available suggesting whether there is such an association. OBJECTIVE: To systematically explore possible differences in the formation of and response to clopidogrel active metabolite (CAM) in mice with or without IL-10 gene expression. METHODS: A single oral dose of clopidogrel (10 mg kg(-1)) was given to IL-10 knockout (KO) mice and wild-type (WT) control mice, respectively, and pharmacokinetic parameters of clopidogrel and CAM were calculated. Moreover, adenosine diphosphate-induced whole-blood platelet aggregation was measured in mice receiving 0, 5, 10, or 20 mg kg(-1) of clopidogrel, respectively. RESULTS: Compared with IL-10 KO mice, WT mice had significantly lower area under the plasma concentration-time curve (AUC) of CAM as a result of a shorter mean elimination half-life but had significantly higher AUC of clopidogrel due to slower systemic clearance and smaller volume of distribution. Although AUC of CAM was significantly lower in WT mice than in KO mice, antiplatelet effects of clopidogrel did not differ significantly between the two mouse groups, as their maximum plasma concentrations (Cmax ) of CAM were not significantly different. CONCLUSIONS: IL-10 expression level affects AUC rather than Cmax of CAM, but the Cmax of CAM is the major driver of antiplatelet effects of clopidogrel in mice.
Subject(s)
Blood Platelets/drug effects , Interleukin-10/blood , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Ticlopidine/analogs & derivatives , Activation, Metabolic , Animals , Area Under Curve , Blood Platelets/metabolism , Clopidogrel , Genotype , Interleukin-10/deficiency , Interleukin-10/genetics , Metabolic Clearance Rate , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Platelet Aggregation Inhibitors/blood , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Function Tests , Ticlopidine/blood , Ticlopidine/pharmacokinetics , Ticlopidine/pharmacologyABSTRACT
A previous study showed that intra-CAl infusion of the beta-adrenergic antagonist DL-propranolol interfered with consolidation of memory for contextual fear conditioning (J.-Z. Ji, X.-M. Wang, & B.-M. Li, 2003). The present study investigated the effect of similarly administered DL-propranolol on consolidation of spatial memory for the water maze. DL-propranolol infused 5 min, but not 6 hr, posttraining caused a deficit in 48-hr memory for the spatial water maze task, whereas similarly administered D-propranolol, which has an equipotent "local-anesthetic" activity but significantly lower beta-blocking activity, induced no amnesia. However, DL-propranolol administered 5 min posttraining did not impair 48-hr memory for the cued water maze task. Thus, beta-adrenoceptor in area CA1 is involved in regulating consolidation of spatial memory for the water maze.
Subject(s)
Hippocampus/drug effects , Maze Learning/physiology , Memory/physiology , Receptors, Adrenergic, beta/physiology , Space Perception/physiology , Adrenergic beta-Antagonists/administration & dosage , Analysis of Variance , Animals , Cues , Instillation, Drug , Male , Maze Learning/drug effects , Memory/drug effects , Propranolol/administration & dosage , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic, beta/drug effects , Space Perception/drug effects , Spatial Behavior/drug effects , Spatial Behavior/physiology , Time FactorsABSTRACT
Nitric oxide (NO) is a well-known vaso-dilator but its regulation in the retina is unclear. This study was conducted to quantify total NO production and retinal ganglion cell (RGC) loss in an experimental glaucoma model. Three quarters of the peri-limbal/episcleral drainage vessels and anterior angle (right eyes) of Sprague-Dawley rats were thermally blocked using laser irradiation, while the left eyes served as controls. We measured the intraocular pressure (IOP) of both eyes using a digital tonometer (Tonopen) 21, 28 and 35 days after the laser treatment. After 35 days, we determined the total NO level in retinas and remaining ocular tissues for the laser-treated and control eyes using a spectro-photometric assay. The viable RGC numbers were also determined by counting the cell bodies stained retrogradely by fluoro-gold. The laser treatment significantly increased the IOP 2.0-2.6x throughout the whole periodof measurements (P<0.0001). The mean total RGC number decreased significantly from 98725+/-5383 (+/-S.E. (M.)) to 69276+/-5592, or 29.8% reduction, in the laser-treated eyes after 35 days (P=0.008). The mean total NO level in the laser-treated retina was significantly increased by 2.4x compared with controls (P=0.016), but no significant difference was found in the eyecups (P>0.05). Laser treatment resulted in significant IOP elevation and RGC loss, suggesting that thermal coagulation of the perilimbal region may provide an alternate protocol for glaucoma study. NO level was increased by two-fold in the retina but not in other ocular tissues. Since NO is capable of producing powerful peroxynitrite anions and hydroxyl radicals, elevated level of NO has a potential role in glaucoma.
